AAV Mediated Angiogenic Therapy for Coronary Disease

超出所提供的空间。目前用血管成形术或冠状动脉搭桥术治疗冠状动脉功能不全，约三分之一的病例可能并发再狭窄。促进血管生长的血管生成因子如VEGF和FGF的发现刺激了使用它们治疗冠心病的研究。直接注射生长因子只产生短暂效应。目前正在测试以浆DNA形式或通过腺病毒载体递送的编码血管生成因子的基因。我们建议通过AAV载体递送编码血管生成因子的基因。AAV似乎是用于递送血管生成因子的理想载体，因为它是非致病性的。已经显示肌肉内注射AAV载体是递送分泌蛋白如促红细胞生成素和因子IX的有效方式。我们的初步研究表明，通过AAV载体递送到心肌中的VEGF可以刺激冠状动脉闭塞的小鼠心肌中的新血管生长。本提案的目的是：（1）我们将通过使用大鼠模型以及小鼠来验证和扩展这些初步发现;大鼠是因为对冠状动脉闭塞的病理生理后果有了更好的理解，并且测量它们的技术已经很好地建立;小鼠是因为冠状动脉血管的三维结构可以通过新的CT技术可视化。AAV递送的血管生成因子对左心室功能的影响将通过超声心动图和用压力-容积导管测量来确定。(2)我们将调节血管生成因子基因的表达，以避免过度表达，这可能会导致血管瘤的形成。首先将研究Epo和VEGF基因的缺氧反应元件。或者，也将测试其他诱导系统。(3)我们将比较单独和不同组合的VEGF和血管生成素基因的AAV递送的有效性。这些研究可能为治疗冠状动脉功能不全提供一种有效的方法。加州大学弗朗西斯科分校（UCSF），弗朗西斯科，加州关键人员=

EXCEED THE SPACE PROVIDED. Current treatment of coronary insufficiency with angioplasty or coronary bypass could be complicated by restenosis in about one third of the cases. The discovery of angiogenic factors that promote blood vessel growth such as VEGF and FGF has stimulated the investigation of using them for the treatment of coronary disease. Direct injection of the growth factors only produces transient effect. The gene encoding for angiogenic factors delivered in the form of plasmic DNA, or by adenoviral vectors are currently being tested. We propose to deliver the genes encoding for angiogenic factors by AAV vectors. AAV appears to be an ideal vector for the delivery of angiogenic factors as it is nonpathogenic. Intramuscular injection of AAV vectors has been shown to be an efficient way of delivering secretory proteins such as erythropoietin and Factor IX. Our preliminary studies indicate that VEGF delivered by AAV vectors into the myocardium can stimulate new blood vessel growth in the myocardium of mice with occluded coronary arteries. The aims of this proposal are: (1) We will verify and extend these preliminary findings by using a rat model in addition to the mouse; rat because the pathophysiologic consequences of coronary occlusion are better understood and the techniques for measuring them well established; and mice because the 3 dimensional structure of the coronary vasculature can be visualized by a new CT technique. Effect of AAV delivered angiogenic factors on left ventricular functions will be determined by echocardiography and measurement with the pressure-volume catheter. (2) We will regulate the expression of the genes for angiogenic factors to avoid overexpression which may cause angioma formation. The hypoxia responsive element of the Epo and VEGF gene will first be investigated. Alternatively, other inducible system will also be tested. (3) We will compare the effectiveness of AAV delivery of the genes for VEGF and angiopoietins, alone and in different combinations. These studies may lead to an effective approach for the treatment of coronary insufficiency. University of California, San Francisco (UCSF), San Francisco, California KEY PERSONNEL ========================================Section End===========================================